A Safety, Pharmacokinetic and Clinical Activity Study of NUC-7738 in Patients With Advanced Solid Tumours and Lymphoma

Lymphoma Clinical Trial

Official title:

A Phase I/II, Open-label, Dose-escalation and Expansion Study to Assess the Safety, Pharmacokinetics and Clinical Activity of NUC-7738, a Nucleotide Analogue, in Patients With Advanced Solid Tumours and Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03829254
• Other study ID #: NuTide:701
• Secondary ID: 2018-003417-17
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 17, 2019
• Est. completion date: June 2024

Study information

• Verified date: March 2024
• Source: NuCana plc
• Contact: NuTide:701 Project Manager
• Phone: +44 (0)131 357 1111
• Email: NuTide701[@]nucana.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase I/II, dose-escalation and expansion study of NUC-7738 administered by intravenous infusion as a monotherapy and in combination with pembrolizumab.

In Phase I, NUC-7738 monotherapy is evaluated across two administration schedules (weekly or fortnightly) in a dose-escalation design in patients with advanced solid tumours. The main objectives are to assess the safety and tolerability of NUC-7738, in addition to establishing the Maximum Tolerated Dose (MTD) and dose administration schedule of NUC-7738 for further exploration in the Phase II part of the study.

In Phase II, the selected dose and designated dosing schedule will be further evaluated in expansion cohorts enrolling a total of approximately 40 additional patients with advanced solid tumours. Based on emerging data, approximately 6 patients with cutaneous melanoma will be enrolled to these expansion cohorts and will receive NUC-7738 monotherapy. A further cohort will assess NUC-7738 in combination with pembrolizumab in approximately 6-12 patients with cutaneous melanoma. In addition, 12 patients with lymphoma (with potential expansion to a total of 25 patients) may be enrolled to receive NUC-7738 monotherapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 94
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Provision of signed written informed consent

2. Solid tumour cohorts only (Phase I and Phase II; excluding NUC-7738 + pembrolizumab cohort): Histologically confirmed diagnosis of an advanced solid tumour with measurable disease as per RECIST v1.1 criteria and/or evaluable disease (evaluable: cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions, which do not fulfil RECIST v1.1 criteria for measurable disease) for solid tumours

3. NUC-7738 + pembrolizumab cohort only (Phase II): Histologically confirmed diagnosis of cutaneous melanoma with measurable disease as per RECIST v1.1 criteria. Must have progressed on =2 prior lines of therapy for advanced/metastatic cutaneous melanoma, that may have included 1 prior line of an immunotherapy-containing regimen (either monotherapy or in combination with chemotherapy). Patients who have not progressed but where addition of NUC 7738 to standard pembrolizumab monotherapy may be appropriate are also eligible.

4. Lymphoma cohort only (Phase II): Relapsed refractory lymphoma (high grade and low grade B-NHL, Hodgkin's Lymphoma and T-cell lymphomas), which is not amenable to standard of care, is refractory to standard of care or for which no standard of care exists. Patients must have bi-dimensionally measurable disease as per Cheson et al, 2007 criteria for lymphoma.

5. For solid tumours in Phase II only: patients should have received no more than 3 prior lines of treatment for metastatic disease.

6. Age =18 years (no upper age limit)

7. Eastern Cooperative Oncology Group performance status of 0 or 1

8. Life expectancy of =12 weeks

9. Adequate bone marrow, liver, and renal function

10. Ability to comply with protocol requirements

11. Female patients of child-bearing potential must have a negative serum pregnancy test within 3 days prior to the first NUC-7738 administration. All patients of child-bearing potential must agree to practice true abstinence or to use two forms of contraception, one of which must be a highly effective method of contraception, from the time of screening until 6 months after the last dose of study medication.

12. Patient must be willing to undergo a new tumour biopsy at Screening and during therapy on the study. Biopsies are mandatory for patient inclusion, except where taking a biopsy would be associated with unacceptable clinical risk due to the location of the disease. Such patients may be discussed on a case-by-case basis with the study Medical Monitor to determine their eligibility. A prior (archival) biopsy that is less than 3 months old may be substituted for a fresh tumour biopsy at Screening with agreement from the Medical Monitor.

13. Patients must have been advised to take measures to avoid or minimise exposure of the skin and eyes to UV light, including avoiding sunbathing and visits to the solarium, for the duration of study participation and for a period of 4 weeks following the last dose of study medication.

Exclusion Criteria:

The following exclusion criteria apply to all patients. Please also refer to additional exclusion criteria for the NUC-7738 + pembrolizumab cohort below.

1. History of allergic reaction fo any of the components of NUC-7738

2. Symptomatic central nervous system or leptomeningeal metastases

3. Chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy for bone pain), immunotherapy, or exposure to another investigational agent within 28 days (for biological agents decision on washout period will be made on a case by base basis) of first administration of the IMP:

1. For nitrosoureas and mitomycin C within 6 weeks of first administration of NUC-7738

2. For hormone therapy within 14 days of first administration of NUC-7738

3. Corticosteroid treatment is allowed during the screening period but should be weaned to a dose of 10 mg prednisolone (or steroids equivalent) by Cycle 1 Day 1.

4. Phase II only; prior treatment with CAR-T cells

5. Prior toxicities from anti-cancer agents or radiotherapy, which have not regressed to Grade =1 severity (NCI-CTCAE v5.0), excluding neuropathy, ototoxicity and alopecia (which are excluded if =Grade 3).

6. Presence of any uncontrolled concomitant illness, serious illness, medical conditions, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with their participation in the study, or with the interpretation of results, including the following:

1. Congestive heart failure (New York Heart Association Class III or Class IV)

2. Myocardial infarction within 6 months of the first dose of study medication

3. Unstable or poorly controlled angina pectoris

4. Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiogram finding

5. A history of or current risk factor for Torsades de Point (e.g., heart failure, hypokalaemia, or a family history of long QT syndrome)

6. A history of, or current diagnosis of, interstitial pneumonitis or pulmonary fibrosis

7. Known human immunodeficiency virus positive or known active hepatitis B or C. Presence of an active bacterial or viral infection including Herpes zoster or chicken pox

8. Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location etc.) that, in the judgment of the Investigator, may affect the patient's ability to sign the informed consent and undergo study procedures

9. Currently pregnant, lactating or breastfeeding

10. QTc interval >450 milliseconds for males and >470 milliseconds for females

11. Concomitant use of drugs known to prolong QT/QTc interval

12. Concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors. The use of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or the use of strong CYP3A4 inhibitors within 1 week of first receipt of study drug is also excluded.

13. Have received a live vaccination within four weeks of first planned dose of study medication.

NUC-7738 + pembrolizumab cohort only

1. Any history of hypersensitivity or current contra-indication to the components of pembrolizumab (L-histidine, polysorbate 80, sucrose, sodium hydroxide, hydrochloric acid)

2. Current contra-indication to immunotherapy with checkpoint inhibitors.

3. Systemic steroid therapy or any immunosuppressive therapy (=10 mg/day prednisone or equivalent).

4. Known neutralising antibodies against checkpoint inhibitors.

5. Patients previously exposed to checkpoint inhibitors who are not adequately treated for skin rash or have no replacement therapy for endocrinopathies.

6. Any prior toxicity attributed to checkpoint inhibitors that resulted in discontinuation of therapy

7. Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease or any condition that requires systemic steroids.

Related Conditions & MeSH terms

• Advanced Cancer
• Lymphoma
• Solid Tumor

Intervention

Drug:
• NUC-7738
NUC-7738
• Pembrolizumab
Pembrolizumab

Locations

Country	Name	City	State
United Kingdom	University of Edinburgh	Edinburgh
United Kingdom	The Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Freeman Hospital	Newcastle
United Kingdom	University of Oxford	Oxford

Sponsors (1)

Lead Sponsor	Collaborator
NuCana plc

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with dose-limiting toxicities	Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours	From the date of consent until 30 days after the last dose of NUC-7738 administered
Primary	Number of patients with treatment-emergent adverse events (CTCAE v5.0)	Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours	From the date of consent until 30 days after the last dose of NUC-7738 administered
Primary	Number of patients with clinically significant laboratory changes (CTCAE v5.0)	Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours	From the date of consent until 30 days after the last dose of NUC-7738 administered
Primary	Number of patients with changes in physical exam, vital signs, and serial electrocardiograms.	Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours	From the date of consent until 30 days after the last dose of NUC-7738 administered
Primary	MTD for NUC-7738 administered via weekly and fortnightly dosing schedules in patients with advanced solid tumours	Phase I	Until completion of Phase I (an average of 1 year)
Primary	Percentage change from baseline in tumour size	Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007)	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)
Primary	Objective response rate (ORR)	Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007): defined as the number of patients achieving a confirmed response (complete response [CR] or partial response [PR])	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)
Primary	Duration of response (DoR)	Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for CR or PR until the first date that recurrence or progressive disease (PD) is objectively documented (responders only)	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)
Primary	Disease control rate (DCR)	Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007): defined as the proportion of patients achieving confirmed response (CR and PR) or stable disease (SD) as the best overall response	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)
Primary	Duration of stable disease (DoSD)	Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for SD until the first date that recurrence or PD is objectively documented	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)
Primary	Progression free survival (PFS)	Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007): defined as the time from first dose of study treatment until the date of objective disease progression or death	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)
Secondary	Phase I: Plasma concentration of NUC-7738 at end of infusion (Cinf)		Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (cycle: 14 days).
Secondary	Phase I: Maximum observed plasma concentration (Cmax) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (cycle: 14 days).
Secondary	Phase I: Area under the plasma concentration-time curve (AUC) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (cycle: 14 days).
Secondary	Phase I: Elimination half-life (t½) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase I: Volume of distribution of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase I: Clearance of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase II: Plasma concentration of NUC-7738 at end of infusion (Cinf)		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase II: Maximum observed plasma concentration (Cmax) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase II: Area under the plasma concentration-time curve (AUC) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase II: Elimination half-life (t½) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase II: Volume of distribution of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Phase II: Clearance of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738		Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)
Secondary	Percentage change from baseline in tumour size	Phase I: Efficacy (per RECIST v 1.1 or Cheson et al, 2007); The percentage change in the sum of longest diameters of target lesions from baseline to Week 8.; The best percentage change in the sum of longest diameters of target lesions from baseline to best on-treatment measurement	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
Secondary	ORR	Phase I: Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the number of patients achieving a confirmed response (complete response [CR] or partial response [PR])	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
Secondary	DoR	Phase I: Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for CR or PR until the first date that recurrence or progressive disease (PD) is objectively documented (responders only)	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
Secondary	DCR	Phase I: Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the proportion of patients achieving confirmed response (CR and PR) or stable disease (SD) as the best overall response	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
Secondary	DoSD	Phase I: Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for SD until the first date that recurrence or PD is objectively documented	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
Secondary	PFS	Phase I: Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from first dose of study treatment until the date of objective disease progression or death	Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
Secondary	Number of patients with treatment-emergent adverse events (CTCAE v5.0)	Phase II: Safety and tolerability of NUC-7738 as a single-agent or in combination with pembrolizumab in patients with advanced solid tumours and lymphoma	From the date of consent until 30 days after the last dose of NUC-7738 administered
Secondary	Number of patients with clinically significant laboratory changes (CTCAE v5.0)	Phase II: Safety and tolerability of NUC-7738 as a single-agent or in combination with pembrolizumab in patients with advanced solid tumours and lymphoma	From the date of consent until 30 days after the last dose of NUC-7738 administered
Secondary	Number of patients with changes in physical exam, vital signs, and serial electrocardiograms.	Phase II: Safety and tolerability of NUC-7738 as a single-agent or in combination with pembrolizumab in patients with advanced solid tumours and lymphoma	From the date of consent until 30 days after the last dose of NUC-7738 administered